Cyclic nucleotide such as cAMP, cGMP, etc. are involved in regulations of many in vivo functions as the second messenger in the intracellular signal transduction (Kukovetz et al., Naunyn Schmiedeberg's Arch. Pharmacol., Vol. 310, pp. 129-138, 1979; Schram et al., Science, Vol. 225, pp. 1350-1356, 1984; Ignarro et al., Annu. Rev. Pharmacol. Toxicol., Vol. 25, pp. 171-191, 1985; Martin et al., J. Pharmacol. Exp., Vol. 237, pp. 539-547, 1986).
Intracellular concentrations of the cAMP and cGMP, changing in response to an extracellular signal, are regulated by a balance between adenylcyclase and guanylcyclase involved in a synthesis thereof, and phosphodiesterase (PDE) involved in a hydrolysis of cyclic nucleotides.
Until recently, many phosphodiesterases have been found from tissues of mammals which hydrolyze cyclic nucleotides, and they have been classified into plural types, according to homology of amino acid sequence, biochemical properties, characterization by an inhibitor, etc. (Beavo, Physiol.Rev., Vol 75, pp. 725-748, 1995).
For example, PDE1 is Ca2+/calmodulin dependent PDE and hydrolyses both cAMP and cGMP. PDE2 is activated by cGMP and hydrolyses both cAMP and cGMP. PDE classified as PDE3 is inhibited by cGMP. PDE4 specifically recognizes cAMP as a substrate, and is Rolipram-sensitive. PDE5 specifically recognizes cGMP as a substrate. PDE6 is a photoreceptor cGMP-PDF. PDE7 specifically recognizes cAMP as a substrate, and is not sensitive to Rolipram.
Further recently, existences of 3 kinds of novel types of PDE have been reported. One is called PDE8, specifically recognizing cAMP as a substrate, and another is called PDE9, specifically recognizing cGMP as a substrate (Soderling et al., Proc. Natl. Acad. Sci. USA, Vol. 95, pp. 8991-8996, 1998; Fisher et al., Biochem. Biophys. Res. Commun., Vol. 246, pp. 570-577, 1998; Soderling et al., J. Biol. Chem., Vol. 273, pp.15553-15558, 1998; Fisher et al., J. Biol. Chem., Vol. 273, pp. 15559-15564, 1998; Hayashi et al., Biochem. Biophys. Res. Commun., Vol. 250, pp. 751-756, 1998). These two PDEs are reported to be insensitive to IBMX (3-isobutyl-1-methylxanthine). Still another one is called PDE10, recognizing both cAMP and cGMP as a substrate. However, it has been reported to show stronger affinity toward cAMP (Fujishige et al., J. Biol. Chem., Vol. 274, pp. 18438-18445, 1999; Kotera et al., Biochem. Biophys. Res. Commun., Vol., 261, pp. 551-557, 1999).
Also, PDE is an important target compound for research and development in a pharmaceutical field, and research on its inhibitor has been earnestly carried out. Among the known pharmaceuticals, there have been found those having an inhibitory action on PDE, and also, it has been found that a specific PDE inhibitor can serve as a useful therapeutic agent.
For example, Milrinone and Zaprinast as a cardiac are inhibitors of PDE3 and PDE5, respectively (Harrison et al., Mol. Pharmacol., Vol. 29, pp. 506-514, 1986; Gillespie et al., Mol. Pharmacol., Vol. 36, pp. 773-781, 1989). Also, Rolipram whose antidepressant activity has been reported is a PDE4 inhibitor (Schneider et al., Eur. J. Pharmacol., Vol. 127, pp. 105-115, 1986). PDE4 inhibitor has been also developed and tested as an anti-inflammatory agent or an antasthmatic agent.
On top of that, IBMX is known as a non-selective type inhibitor acting on many types of PDEs. Vinpocetine is known to be a PDE1 inhibitor, EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine] is known to be a PDE2 inhibitor, Dipyridamole is known to be an inhibitor of PDE5 and PDE6. Also, SCH51866 ((+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo-[2,1-b]purin-4-one; U.S. Pat. No. 5,939,419) is known to be an inhibitor of PDE1 and PDE5, and E4021 (sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl]pyperidine-4-carboxylate; CAS Registration No. 150452-19-0) is known to be an inhibitor of PDE5.
For development of an excellent pharmaceutical with a high therapeutic effect and less side effect, it is expected to choose an inhibitor having a high selectivity toward a certain type of PDE as a target.
Moreover, it has been sought to find a novel type of PDE, being a different molecular species from the known ones, for studying a complex mechanism of intracellular signal transduction, and also, for a possibility to become a target molecule of a new therapeutic agent.
An object of the present invention is to provide a novel type of phosphodiesterase [Type 11 phosphodiesterase (PDE11)] and its gene. Also, it is to provide a novel method for characterizing, identifying or selecting a phosphodiesterase inhibitor. Further, other objects than the above will be clear from the following descriptions.